Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity

Alberto Toso, Ajinkya Revandkar, Diletta DiMitri, Ilaria Guccini, Michele Proietti, Manuela Sarti, Sandra Pinton, Jiangwen Zhang, Madhuri Kalathur, Gianluca Civenni, David Jarrossay, Erica Montani, Camilla Marini, Ramon Garcia-Escudero, Eugenio Scanziani, Fabio Grassi, PierPaolo Pandolfi, Carlo V. Catapano, Andrea Alimonti

Research output: Contribution to journalArticlepeer-review

Abstract

Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of theprotein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.

Original languageEnglish
Pages (from-to)75-89
Number of pages15
JournalCell Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Oct 9 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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